LEF-1 Internal Ribosome Entry Site
Background: Full length Lymphoid Enhancer Factor-1 (LEF-1) is a transcription factor that promotes cell growth via its interaction with the WNT signaling mediator beta-catenin. Truncated LEF-1 lacks the beta-catenin binding domain and opposes WNT signaling as a competitive inhibitor for WNT response elements. Numerous types of cancers derive from overactive WNT signaling.
University of California researchers studied the post-transcriptional regulation of Lymphoid Enhancer Factor-1. Initiation of translation in eukaryotic cells can occur by two distinct mechanisms, cap-dependent scanning from the 5' end of the messenger RNA (mRNA) and internal ribosome entry (cap-independent translation). Internal ribosome entry occurs via an internal ribosome entry site (IRES) element present in the sequences of certain viral and cellular mRNAs. It was discovered that an IRES mediates translation of full length LEF-1.
Technology: University of California, Irvine researchers have found that LEF-1 mRNA exhibits internal ribosome entry site (IRES) activity through DNA and RNA transfections of a dicistronic vector containing the LEF-1 5' UTR sequences. Researchers found that the 5' UTR of human LEF-1 mRNA contains two independent IRES modules that are additive in their mediation of cap-independent translation of full length LEF-1 protein.
The second module appears to carry greater activity than the first IRES module. Researchers also found that the LEF-1 IRES has six fold greater activity when compared with the activity of Kv1.4 channel IRES and two fold greater activity when compared with the CVB4 IRES in COS-1 cells. The IRES element is GC-rich, devoid of AUG codons in any frame except for one, and will work in both the nucleus and in the cytoplasm with maximal IRES activity in the nucleus.
Application: The LEF-1 IRES element may be used to express two transgenes proportionally in a biscistronic vector by inserting the IRES between two genes (e.g. a gene of interest and a reporter gene). The LEF-1 IRES element might also be used in expression of genes in vectors for gene therapy or other therapeutic purposes. Due to its important role in WNT signaling and differentiating cells, the LEF-1 IRES element should also be of interest to cancer and WNT signaling research groups.
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